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Identification of PSD-95 as a regulator of dopamine-mediated synaptic and behavioral plasticity.

To identify the molecular mechanisms underlying psychostimulant-elicited plasticity in the brain reward system, we undertook a phenotype-driven approach using genome-wide microarray profiling of striatal transcripts from three genetic and one pharmacological mouse models of psychostimulant or dopamine supersensitivity. A small set of co-affected genes was identified. One of these genes encoding the synaptic scaffolding protein PSD-95 is downregulated in the striatum of all three mutants and in chronically, but not acutely, cocaine-treated mice. At the synaptic level, enhanced long-term potentiation (LTP) of the frontocortico-accumbal glutamatergic synapses correlates with PSD-95 reduction in every case. Finally, targeted deletion of PSD-95 in an independent line of mice enhances LTP, augments the acute locomotor-stimulating effects of cocaine, but leads to no further behavioral plasticity in response to chronic cocaine. Our findings uncover a previously unappreciated role of PSD-95 in psychostimulant action and identify a molecular and cellular mechanism shared between drug-related plasticity and learning.

Pubmed ID: 14980210

Authors

  • Yao WD
  • Gainetdinov RR
  • Arbuckle MI
  • Sotnikova TD
  • Cyr M
  • Beaulieu JM
  • Torres GE
  • Grant SG
  • Caron MG

Journal

Neuron

Publication Data

February 19, 2004

Associated Grants

  • Agency: NIDA NIH HHS, Id: DA13511

Mesh Terms

  • Animals
  • Behavior, Animal
  • Brain
  • Cocaine
  • Cocaine-Related Disorders
  • Dopamine
  • Down-Regulation
  • Guanylate Kinase
  • In Vitro Techniques
  • Intracellular Signaling Peptides and Proteins
  • Long-Term Potentiation
  • Membrane Proteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Motor Activity
  • Nerve Tissue Proteins
  • Neural Pathways
  • Neuronal Plasticity
  • Nucleus Accumbens
  • Presynaptic Terminals
  • RNA, Messenger
  • Reward
  • Synaptic Transmission